This project investigates an apoptosis-inducing, gene therapy approach for advanced pancreatic cancer using C-VISA BikDD:liposome (BikDD nanoparticle). This agent consists of a mutated, pro-apoptotic Bik gene termed as BikDD, a modified pancreatic-specific CCKAR promoter, an amplifier Two-Step Transcriptional Activation System (TSTA)-Woodchuck Hepatitis Post-Transcriptional Regulatory Element (WPRE) and is encapsulated by the DOTAP:Cholesterol liposome. The BikDD nanoparticle specifically targets transgene expression in pancreatic adenocarcinoma, both in vitro and in vivo. In vivo toxicity studies of the BikDD nanoparticle have revealed this to be a safe therapy as compared with CMV-BikDD. The phase I clinical study will be conducted for patients with advanced, unresectable pancreatic adenocarcinoma with adequate laboratory function and performance status [Eastern Co-operative Oncology Group 0-1]. Enrolled patients should have received gemcitabine previously, have liver metastasis and be willing to undergo paired biopsies. The starting dose of the BikDD nanoparticle will be 0.04 mg/kg and is the human equivalent of one tenth of the highest dose tested in the mouse single dose toxicity test. Dose levels are 0.04, 0.05, 0.06 mg/kg. If dose limiting toxicity is experienced at dose level 1, de-escalation by 33% is permitted. If maximum tolerated dose (MTD) is not reached at 0.06 mg/kg, further escalation by 33% increments will occur. The BikDD nanoparticle will be administered on a weekly schedule as an intravenous infusion. Dose escalation to the next higher level will be permitted only if adequate safety and tolerability have been demonstrated in the preceding cohort. Dose escalation will utilize the 3+3 dose escalation scheme until the MTD is reached. Biopsies will be obtained from liver metastasis before and on day 24 of therapy and will be analyzed for BikDD expression, apoptotic index (AI) and caspase-3 expression. Blood samples will be drawn for pharmacokinetic studies for BikDD DNA (copies/ml) on day one. Biologically Active Dose Range (BADR) will be defined as the dose range at which increased AI is observed over baseline. Tumor re- assessments using appropriate radiological studies will be conducted periodically;treatment will continue until there is evidence of toxicity or progressive disease. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is one of the most lethal of human cancers ranking as the fourth leading cause of cancer mortality in the United States. The majority of patients with pancreatic cancer has an advanced stage of disease at diagnosis and therefore is not candidates for surgical resection. The overall goal of this project is to investigate a gene therapy approach against this malignancy in a clinical study.